EXPERIMENTALSTUDYOF CLINICAL VITAMIN B DEFICIENCY1

By KATHARINEO'SHEA ELSOM

(From the Gastro-Intestinal Section of the Medical Clinic, Hospital of the University of Penn-sylvania, and the John Herr Musser Department of Research Medicine,

University of Pennsylvania, Philadelphia)

(Received for publication August 27, 1934)

Clinical disturbances incident to mild deficiencyof vitamin B 2 in the diet, as opposed to frankdeficiencies such as beriberi and pellagra, are com-monly believed to be very rare in man and arethought to occur only when the diet is grossly ab-normal or when there is serious interference withabsorption from the gastro-intestinal tract. Cer-tain observations made in this Gastro-IntestinalSection, however, have suggested that clinical evi-dences of such partial deficiency may develop on

given for the first five months a diet moderatelydeficient in vitamin B though adequate in everyother known requirement and the effects of thisdiet were studied. When clinical signs suggestiveof deficiency were manifest, various vitamin Bfractions were added to the diet, in series, and theeffects of their administration studied. The sec-ond patient (Case 2), who entered the hospitalwith fully developed clinical evidence of defi-ciency, was likewise placed on a diet restricted in

CerealsCream of wheat

RiceWhite cornmeal

TABLE IChart showing articles composing the diet deficient in the vitamin B complex

Meat VLamb PotE

VealBeef (50 grams twice weekly)

TuriCor:SpinOnihBeeCabRut.Car

regetablesatoes: white

sweetnips*niach 1on

tbsage rBoiled 2 hours:abagarots J

FruitOrange juice: 100 grams daily

ApplePearGrapeCocoanut

Pastry and desserts

Cornstarch pudding } without milkJelloPie: apple

pearCake with white flourBiscuits J and without milk or eggJelly: grape

apple

FatsButterCod liver oil: 10 grams dailyLard

a diet which is not obviously abnormal and in theabsence of serious gastro-intestinal disease. Ex-periments to test this hypothesis were carried outon two patients, one of whom (Case 1) was hos-pitalized for approximately a year. She was

1 Aided by a grant from the Faculty Research Commit-tee of the University of Pennsylvania.

2The term vitamin B as used in this paper includes allmembers of the vitamin B complex; individual membersare referred to as B1, 12 (G), and the "additional fac-tors ": B,, B,, and factor Y.

BeveragesTeaCoffee

Seasonings as desiredChocolate, cinnamon,molasses, salt, etc.

its content of vitamin B and was studied duringthe addition to it of separate vitamin B fractions.

METHODSOF STUDY

The articles of which the experimental diet wascomposed are recorded in Table I.8

8The vitamin B, content of the diet for Case 1 wascalculated by Dr. George Cowgill according to a formulaof his as yet unpublished, and was found to contain ap-proximately one-half of the theoretical vitamin B, re-quirement.

40

CLINICAL VITAMIN B DEFICIENCY

All food was weighed. Caloric, fluid and pro-tein intake was constant throughout the entire ex-periment, the latter intake amounting to 49 gramsper day for Case 1, and 68 grams for Case 2.Daily output of urine was measured. Symptomsand physical signs were recorded daily. Mouthtemperature was taken morning and evening.The patients were weighed daily under standardconditions on a balance accurate to within 8grams. Nitrogen balance was determined during2 three-day periods, both food and excreta beinganalyzed. Roentgen examination of the gastro-intestinal tract was made at the beginning andend of each experimental period; observations ofthe level and tone of the stomach, of the type ofperistalsis, and of the motility throughout thesmall intestine and colon were made every twohours for six hours. Fractional gastric analyseswere carried out using oatmeal gruel as the testmeal. Exercise tolerance tests (1) were per-formed during each experimental period. Bloodpressure and pulse rate were measured under ba-sal conditions and repeated on standing and afterclimbing 54 steps at maximal speed. Serumprotein analyses, enumeration of red blood cells,hemoglobin estimations (2) and hematocrit read-ings, carried out under conditions which insuredcomplete packing of cells, were made weekly.Venous pressure was measured from accessibleveins on the dorsum of the hand by the indirectmethod of Krogh, Turner and Landis (3). De-termination of capillary permeability was made inCase 1 at the height of the edema using the pro-cedures described by Landis, Jonas, Angevine andErb (4). Respiratory quotient, basal metabolicrate, electrocardiograms, orthodiagrams, tests ofrenal function, platelet counts, sugar tolerancetests and estimations of coagulation time weremade in the routine hospital laboratories.

The vitamin B1 substance 4 was prepared as an80 per cent alcoholic extract of wheat embryo ac-cording to the method of Bourquin and Sherman(5). Using the rat growth method of biologicalassay (6), this extract was found to be free ofother vitamin fractions and to be potent in vita-min B1, 1 cc. of the extract containing approxi-

4Vitamin materials were prepared and assayed in theLaboratory of Physiological Chemistry under the direc-tion of Dr. J. H. Jones, to whom acknowledgement isgratefully made.

mately 21 Sherman units. The required dose ofthis substance for Case 1, 11.3 cc., was calculatedfrom the optimal dose in rats on the basis ofrelative caloric requirements. To be certain ofadequate dosage 20 cc. were given daily for 3weeks, after which the daily dose was increasedto 40 cc. The vitamin B2 concentrate was madefrom egg white by the method of Chick, Coppingand Roscoe (7). It was found to be potent invitamin B2 and free of other vitamin fractions.The calculated human dose was first doubled, 60cc. of the extract being given daily for 2 weeks,and then increased to 120 cc. for the remainderof the experiment. Powdered brewer's yeastconcentrate 5 prepared by a modification of theOsborne and Wakeman method (8) and knownto contain factors in addition to vitamins B1 andB2 necessary for maximal growth in the rat(Figure 2) was used as a source of additional Bfactors. An arbitrary dose of 6 tablespoonfulswas given daily. An extract of rice polishingssuitable for parenteral use,6 shown (9) to be apotent source of vitamin B1 was used for a shorttime in Case 2; the daily dose employed variedfrom 2 to 4 cc.

PROTOCOL

Case 1. A woman, 56 years old, 158 cn. tall, weigh-ing 57.2 kilos, had been admitted one year prior to hos-pitalization as an out-patient to this Section, complainingof anorexia, sore tongue, asthenia, paresthesias in thelower extremities, dyspnea and vertigo. She at thattime gave a history of voluntary restriction of diet for10 years and, as described elsewhere (10), had a baldtongue, exaggerated patellar reflexes, impaired vibratorysensation and edema of the lower extremities. Bloodstudies and gastric analysis were negative. Whole yeastconcentrate was administered at that time for 6 weeks,following which the patient had become symptom freeand was then without physical signs except exaggeratedreflexes and diminished vibratory sensation in the lowerextremities. She had continued in good health through-out the remainder of that year. It was then decided todetermine the effect of moderate limitation of diet athome. This was done for 6 weeks prior to hospitaliza-tion with the result that on admission some impairmentof appetite, slight intermittent edema of the ankles, andoccasional sore tongue were manifest. The strict ex-perimental diet was begun immediately upon admission,

5 Obtained from the Harris Laboratories, Tuckahoe,New York.

6 This material was kindly supplied through the cour-tesy of Dr. A. W. Rhodehamel of the Eli Lilly ResearchLaboratories.

41

KATHARINE O'SHEA ELSOM

May 17, 1933, and was continued until March 29, 1934.For a period of 21 days in August 1933 she was awayfrom the hospital but continued the diet. The times atwhich the various vitamin fractions were added to thediet together with various other data from the case maybe seen in Figure 1.

I.. Ol

q4

ITAMfN B DEfICENT PET

ently been taking an adequate diet in addition to con-siderable quantities of beer, but had induced vomitingseveral times weekly to relieve abdominal distress. Con-stipation persisted, and dyspnea, vertigo, palpitation andedema had developed. Cardiac and renal studies werenegative. Free hydrochloric acid was obtained from the

ITDIET.

W+829YEAST

0~~~*

62 _ _

2?60 rZE>a t

58-

56- .-

.ka

LE. .In .

U6 .L.-.I I .

feAw,r 117irchAF 7790 79 79 IL 176I

I Cl 393 323 5551 1 37 3 358 IFIG. 1. CASE 1. CHANGESIN WEIGHT, EDEMAAND SERUMPROTEIN ON VITAMIN B DEFICIENT

DIET AND FOLLOWINGADMINISTRATION OF VITAMIN B FRACTIONS.Arrows at the top of the chart indicate doubled dosage of vitamin B1 and B2 preparations

respectively. Daily intake of fat and carbohydrate in grams is recorded at the bottom of thechart.

Case 2. A man aged 53 years, weighing 65.1 kilos atthe beginning of observation, had had a long history priorto this admission. In 1924, when first seen in the hos-pital, he complained of epigastric discomfort after eating,and of nausea, vomiting and constipation. Roentgeno-logical study at that time revealed extensive gastric poly-posis and repeated examinations subsequently showed nochange. Gastric analysis, routine blood examinations andall other laboratory studies were negative in 1924. In1927 the symptoms had not changed, except that epi-gastric distress had become sufficiently severe to causethe patient to induce vomiting. All studies were negativeexcept those of the blood, which showed red cells num-bering 3,450,000 and hemoglobin of 85 per cent. In 1930the patient again entered the hospital. He had appar-

stomach only after histamine. Peripheral reflexes wereexaggerated. Red blood cells numbered 3,000,000; thehemoglobin was 64 per cent. On November 13, 1933, hewas again admitted to the hospital because of alternateattacks of constipation and diarrhea, the latter persistingseveral weeks at a time, with 10 or more movementsdaily. His appetite was good, although his dietary hab-its, the induced vomiting, and the epigastric discomfortwere unchanged. Dyspnea, palpitation and vertigo hadincreased. He complained of being easily fatigued. iThetongue was smooth and red. Edema extended to theknees. Tests of renal function and orthodiagram werenegative. An electrocardiogram showed moderate tachy-cardia. Blood pressure was 102/68. He complained of" crawling sensations " in the feet and legs. Reflexes

-1--m . . a I sa

a I

-*l ,

qp-_

.1rild

42

I I 10

CLINICAL VITAMIN B DEFICIENCY

were exaggerated and vibratory sensation greatly im-paired in the lower extremities. Other neurological find-ings were normal. Gastric acid was present in moderateamounts without histamine. Red blood cell count was

3,700,000 with hemoglobin of 75 per cent. Serum proteinwas 4.97 grams per 100 cc. blood. Blood sugar deter-minations and glucose tolerance tests gave normal fig-ures. He remained on the regular ward routine for 19days, during which time no change occurred in symp-tomatology, physical signs or laboratory findings. Fol-lowing this period the experimental observations were

begun (see Figure 6). Diarrhea, induced by sulphatesused in preparation of the egg white extract, made itnecessary to discontinue the administration of that sub-stance. Yeast therapy was begun immediately and thepatient was therefore not observed on vitamin B1 and B2therapy alone. The B2 content of the yeast was supple-mented by 5 eggs daily. Believing that there might beinterference with absorption from the gastro-intestinaltract the vitamin B1 preparation for parenteral use de-scribed above was given intravenously. After 7 weekson the experimental regime he left the hospital, continu-ing the diet and vitamin therapy. He returned 3 timesweekly for observation and intravenous administration ofthe vitamin B1 preparation.

RESULTS

Case 1. The symptoms and physical signswhich developed in the course of the experimentare outlined in Table II. All of the findingslisted in the period " deficient diet " had developedwithin the first 5 weeks of that period, after which

there was a gradual increase in their severity.During the period of deficient diet plus adminis-tration of vitamin B1 improvement was first ob-served 2 weeks after therapy was begun. Mid-way in this period the patient developed an acuteupper respiratory infection accompanied by fever.All manifestations of deficiency became aggra-

vated in spite of increased dosage of the vitaminpreparation. After subsidence of the infectionthe improvement noted during the first 2 weeksreturned. Attention is directed to the fact thatimprovement during administration of vitamin B1and of vitamin B1 and B2 was not continued incertain respects during the end of the latter periodand was resumed only when yeast was added tothe diet. It is to be noted, also, that symptomsof anorexia and epigastric distress were relievedonly when therapy with yeast was begun.

Data relating to body weight, edema and serum

protein are presented in Figure 1. It is worthyof note that during the period of vitamin defi-ciency the body weight decreased while the edemaincreased, whereas during the periods of vitaminadministration increase of weight was accompa-

nied by a disappearance of edema. Serum pro-

tein remained above the critical level for edemathroughout the entire experiment, but an increasewas observed during full vitamin therapy. Nitro-

TABLE II

Symptoms and physical signs present in Case 1 at the conclusion of each experimental period

Pre-hospital Deficient diet Deficient diet + Bi Deficient diet Deficient dietperiod + Bland B2 + Bz + Bs + yeast

(6 weeks) (21 weeks) (12 weeks) (4 weeks) (8 weeks)

Asthenia ............ Moderate Improved No change, later Absentincreased

Sore tongue ......... Slight Severe Severe Absent AbsentAnorexia ............ Moderate Severe Very severe Very severe SlightEpigastric distress .... Severe Very severe Very severe AbsentConstipation Severe Very severe Slight improvement AbsentPains in extremities .. Frequent and Less frequent, less No change, later Infrequent

severe severe increasedParesthesias ......... Frequent Less frequent No change, later Infrequent

increasedAverage temperature, 98 97.2 98 98.1 98.2

* ...............

Tongue ............. Smooth Partial regeneration Normal Normalpapillae

Pallor .............. Pronounced Absent Absent AbsentEcchymoses ......... Numerous* Absent Absent, later scat- Absent

teredEdema.Very slight Extensive Decreased Decreased AbsentReflexes. Exaggerated Exaggerated Exaggerated Less exaggerated Less exaggeratedVibratory sensation Lost except over in- Lost Perceived over ex- Normal

ternal malleoli ternal malleoli

* Ecchymoses varied from 1 to 2 cm. in diameter; they were distributed over forearms and legs.

43

KATHARINE OSHEA ELSOM

gen balance was found positive when vitamin B1was added to the deficient diet. The striking gainin weight observed when the deficient diet andvitamin B1 and B2 preparations were supple-mented by yeast was duplicated in rats renderedvitamin B deficient on a Sherman basal diet (5)and to which the same preparations were fed in

-analogous dosage (see Figure 2).

Red blood cell enumeration, hemoglobin andhematocrit readings made throughout the entireexperiment are shown in Figure 3. Plateletcounts were normal, as was bleeding time. Clot-ting time, determined on 2 occasions during defi-ciency, averaged 13 minutes; at the end of vitamintherapy it was 7 minutes.

Blood pressure changes following standard ex-

FIG. 2. WEIGHTCURVESOF RATS RECEIVING A SHERMANBASAL DIET FREE OF VITAMIN B SUPPLE-MENTEDBY WHEATEMBRYO,EGGWHITE ANDYEAST.

Broken lines indicate growth of animals receiving doubled dosage of egg white.

Venous pressure in Case 1 was between 7 and10 cm. of water. Measurements of the volumeof fluid lost through the capillary wall were madeat venous pressure of 67 mm. mercury and theprotein content of this fluid calculated. The av-erage calculated volume of fluid filtered in 6 ex-periments was 10.5 cc. per 100 cc. blood. Theaverage amount of protein in this filtrate was 1.5gram per 100 cc. These results fall within thenormal limits observed by Landis et al. (4), hencethey provide no evidence of increased capillarypermeability.

ercise are shown in Figure 4. Preliminary con-trol readings showed a variation of 5 mm. mer-cury under the standard conditions of the test.The difference in blood pressure before and aftervitamin therapy is most clearly seen in the read-ing obtained after exercise. Systolic pressure atthe end of the deficient period fell 10 minutes af-ter exercise to 88 mm. mercury but after vitamintherapy it fell only to 130 mm. mercury.

Electrocardiogram, orthodiagram and tests ofrenal function were negative.

The results of roentgen examination of the

44

CLINICAL VITAMIN B DEFICIENCY

gastro-intestinal tract are recorded diagrammati-cally in Figure 5. Gastric atony is representedby failure of the stomach to support the columnof barium well into the fundus. This was noted

marked increase of motility in the small intestine;at the end of two hours there was only a smallgastric residue, the head of the meal had reachedthe cecum, the majority of it being in the ileum;

FIG. 3. CASE 1. CHANGESIN HEMOGLOBIN,CELL VOLUMEAND NUMBEROF RED BLOODCELLSONVrrAMIN B DEFICIENT DIET ANDFOLLOWINGADMINISTRATONOF VITAMIN B FRAcTiONs.

Arrows at the top of the chart indicate doubled dosage of vitamin B1 and B2 preparationsrespectively.

in increasing extent until after the conclusionof the administration of vitamin B1 and B2.Throughout these periods peristalsis was infre-quent, and the waves were shallow; at the endof two hours over one-half the meal still remainedin the stomach; stasis in the small intestine wasevident six hours after giving the barium meal.After yeast therapy there was distinct improve-ment in gastric tone; the stomach was more globu-lar in shape and supported the column of bariumwell into the fundus; peristalsis was active andproduced prompt emptying of the stomach; tenminutes after giving the barium meal considerablematerial had passed into the duodenum and hadprogressed well into the jejunum; there was a

colonic motility was increased, the meal havingadvanced to the splenic flexure at the end of fourhours. These changes in the gastro-intestinaltract seen by fluoroscope took place at the timethat the patient noticed relief from epigastricdistress, a return of appetite and relief fromconstipation.

Gastric analysis at the end of the deficient pe-riod gave normal values for acid.

Blood sugar on two occasions during deficiencyaveraged 83 mgm. per 100 cc. blood. Glucosetolerance test gave normal figures. Respiratoryquotient, determined with the patient at rest, was0.77 and 0.78. After 11 days on a high carbo-hydrate diet the quotient was 0.88. At the end

VITAMIN B DEFICIENT DIET

45

KATHARINE O'SHEA ELSOM

of combined vitamin therapy it was 0.72. Basalmetabolic rate was normal throughout the entireexperiment.

4 kilos on addition of yeast to the diet, on theother hand, has been maintained. Anemia didnot improve during the control period (see Fig-

FIG. 4. CASE 1. VARIATIONS IN DIASTOLIC AND SYSTOLIC BLOODPRESSURE, WHILE AT REST, AFr ASSUM-ING A STANDING POSITION, AND AFTER RAPID ASCENTUP 54 STEPS, WHLEON THE VITAMIN B DEFICIENT DIET,AND DURING THE ADMINISTRATION OF VITAMIN B FRACTIONS.

Each point in a continuous line represents successive readings at 1 minute intervals for 5 minutes. An addi-tional reading was made at the end of 10 minutes after exercise.

Case 2. In Figure 6A are shown the resultsof observations of serum protein, weight, andedema. Total serum protein at the end of thecontrol period was 4.46 grams per 100 cc. blood.Colloid osmotic pressure of the serum calculatedaccording to the formula of Govaerts (11) (12)was 16.2 mm. mercury. When edema first de-creased the total protein was 5.17 grams per 100cc. blood, and when edema was negligible 5.50grams per 100 cc. blood. The calculated osmoticpressure of the serum at this time was 20.2 mm.mercury. Three and one-half months later, areading subsequent to the last one recorded onthe chart, the serum protein was 6.6 grams per100 cc. blood and the osmotic pressure 27.2 mm.mercury. Increase of weight on the control dietwas coincident with increasing edema. Declinein weight following administration of vitamin B1occurred with rapid loss of edema. The gain of

ure 6B). Volume index at this time was 1.14,color index 1.10. During therapy with vitaminB1 there was an increase in hemoglobin, erythro-cytes and cell volume, but no significant change involume or color indexes. At the end of 3 monthsof vitamin B1 and yeast therapy the erythrocyteshad increased in number by 34 per cent, the vol-ume index was 0.89 and the color index 0.90.Pulse rate, systolic and diastolic pressures weretaken under the standard conditions of exerciseused with Case 1 (see Figure 7). The moststriking result was a fall in resting pulse rate.Systolic and diastolic pressures increased slightlyat the same time that the pulse rate decreased.The tongue remained smooth and red throughoutadministration of vitamin B1. One week follow-ing the addition of yeast, regeneration of papillaewas evident and at the end of two weeks thetongue was entirely normal in appearance. Flu-

46

CLINICAL VITAMIN B DEFICIENCY

oroscopic examination of the gastro-intestinaltract during the control period showed the samemarked, irregular filling defect of the stomachnoted in 1924 and believed to be due to gastricpolyposis. The stomach was hypertonic; peri-

implication is clear that definite changes in eitherthe absorption or utilization of food-stuff musthave taken place. The fact that serum proteinincreased during vitamin therapy although theprotein intake remained constant may be attrib-

2HOURS

HOURS

HOURS

L-iX- 1~~~~~~~~~-

DIETB1+B,+YEAST.

1t

L1l

FIG. 5. CASE 1. DIAGRAMMATICREPRESENTATIONOF ROENTGENAPPEARANCEOF THE GAsmo-INTEs-TINAL TRACT DURING THE DIFFERENT EXPERIMENTAL PERIODS, 10 MINUTES, 2, 4 AND 6 HoURs AFTERA BARIUM MEAL.

stalsis was active and produced deep segmenta-tion. The stomach emptied quickly and theopaque medium progressed very rapidly throughboth small and large intestines. There was no

visible change in gastro-intestinal tone or motilityafter 3 months on combined vitamin therapy.

DISCUSSION

The observed increase in weight, one of themost striking results of vitamin therapy, deservescomment. It occurred, associated with positivenitrogen balance, on a constant diet and in theface of loss of edema fluid from the body. The

uted to various factors, namely, to increasedabsorption of protein, increased regeneration ofbody protein or to redistribution of body water.

It is uniformly found in deficiency experimentsin animals that when separate vitamin B fractionsare added to the basal diet there occurs a tempo-rary increment in weight which is not maintaineduntil all necessary factors are included in the diet.Similar temporary increase of weight on additionof vitamins B1 and B2 was observed in Case 1;but this increase was not maintained until yeasttherapy had been begun. Evidence was thus pro-vided that additional factors such as are neces-

47

KATHARINE O'SHEA ELSOM

sary in animals for maximal gain of weight were

likewise required by this patient. That these fac-tors were also necessary for complete relief ofsymptoms was shown when, upon addition ofyeast, symptoms disappeared which had returnedtoward the end of the period with vitamin B1 andB2 combined. Gastro-intestinal symptoms were

relieved only after the addition of yeast and itwas likewise only at this time that gastro-intestinaltone and motility returned to normal.

explanation of the edema exists. After vitamintherapy both patients became free from edema.No apparent reason for this is provided by our

studies. In Case 1, the serum protein had beenconsistently above the concentration thought torepresent the critical level. In Case 2, the edemadisappeared before there occurred what is re-

garded as significant alteration in serum proteinconcentration. The permeability of the capillarywall to protein measured by an indirect method

A BFIG. 6. CASE 2.

A. ALTERATIONS IN EDEMA, WEIGHTAND SERUMPROTEIN ON VITAMIN B DEFICIENT DIET,AND FOLLOWINGADMINISTRATION OF VITAMIN B FRACTIONS.

Daily intake in grams of protein, carbohydrate and fat is recorded at the bottom of thechart. The arrow at the top of the chart indicates the time at which the patient left the hos-pital.

B. ALTERATIONS IN HEMOGLOBIN,CELL VOLUMEANDNUMBEROF RED BLOODCELLS.

It is of interest that both of the patients studiedhad definite edema. In Case 2 a ready explana-tion is at hand in the reduced concentration ofserum protein. In Case 1, however, no obvious

was not increased in Case 1. Protein estimationcarried out on edema fluid obtained from Case 2yielded a figure of 0.31 gram per 100 cc. whichindicates that here likewise the capillary wall was

48

DI. ET DIETBW.V* YEAST

45

U.'

z43

041I39

~3715 -~

14

0312& 0 *

~1101IC ANUARY FDRAV MARCHli.

CLINICAL VITAMIN B DEFICIENCY

not abnormally permeable to protein. It seemsextremely unlikely that the observed abnormalitiesin the cardiovascular system during deficiency,viz., reduction in systolic and diastolic pressuresand tachycardia could have been responsible forthe edema in the absence of signs of cardiac de-compensation and in the presence of normal ve-nous pressure. The fact that capillary pressure

is usually 2 to 3 cm. water above venous pressure(13) permits the assumption that in these patientscapillary pressure was not significantly altered andhence that increased filtration pressure was notresponsible for the edema. An unusual capacityof the tissues to bind sodium chloride and waterhas been postulated in cases of "wet" beriberi(14). Whether such an abnormality existed in

FIG. 7. CASE 2. PULSE, SYSTOLIC AND DIASTOLIC BLOODPRESSURE, ATREST, AFTER ASSUMINGA STANDING POSITION, AND AFTER RAPID ASCENTuP 54 STEPS WHILE ON THE VITAMIN B DEFICIENT DIET AND DURING THEADMINISTRATION OF VITAMIN B FRACTIONS.

Each point in a continuous line represents successive readings at 1 min-ute intervals for 5 minutes. An additional reading was made at the endof 10 minutes after exercise.

49

KATHARINE OSHEA ELSOM

Case 1 was tested by administering 900 cc. of nor-mal saline solution by mouth and observing theduration of the resultant gain in weight. Suchmeasurements were made both at the height ofthe edema and at completion of vitamin therapy.Three days were required in both periods forelimination of the fluid. Applicability of thishypothesis to the present situation therefore seemsunlikely.

The relationship of vitamin B to anemia is notclear. Strauss and Castle (15) have suggestedthat some member of the vitamin B complex, afterinteraction with normal gastric juice may be theactive food factor in prevention of pernicious ane-mia. They and others (16) (17) (18) have ob-tained remissions using various yeast extracts,autolyzed yeast preparations, egg white and othervitamin B substances. It is still uncertain, how-ever, which vitamin B fraction is the activt factorin these responses. Anemia is rarely seen in beri-beri (19), and its occurrence is variable in pel-lagra. There is little evidence that anemia resultsfrom complete vitamin B deficiency in rats (20).Recently, however, Rhoads (21) induced a macro-cytic anemia in dogs following prolonged restric-tion of vitamin B2. In the present investigationboth patients were moderately anemic while in thedeficient state. In Case 1 the anemia was of themicrocytic type. Following vitamin therapy therewas a slow regeneration of hemoglobin and redcells. Anemia in Case 2 was more striking. Atendency toward macrocytosis was observed at theend of the deficient state. At the conclusion ofcombined vitamin B1 and yeast therapy this tend-ency had disappeared. Thus in an individual,Case 1, whose gastro-intestinal function was nor-mal, induced vitamin B deficiency of 6 monthsduration failed to produce significant anemia. InCase 2, however, who suffered impairment ingastro-intestinal function, vitamin B deficiencywas associated with anemia of macrocytic type,which improved following vitamin therapy. It isnoteworthy that signs and symptoms of neuro-logical involvement indistinguishable from thoseof early Addisonian anemia developed in Case 1during the period of deficient diet and disappearedduring vitamin administration. Similar signswere present in Case 2 on admission and likewiseshowed regression on vitamin therapy.

The fact that disturbances of gastro-intestinal

tone and motility in Case 1 developed during de-ficiency and disappeared after therapy justifiesthe conclusion that they are properly attributableto lack of vitamin B. In Case 2, pre-existinggastro-intestinal disease makes difficult the inter-pretation of effects of vitamin deficiency on thegastro-intestinal tract. There is ample evidenceboth in animal experiments and in clinical obser-vations of beriberi and pellagra that severe vita-min B deficiency produces disturbances in gastro-intestinal function. Loss of papillae from thetongue (21) and loss of gastric tone while onvitamin B deficient diets (22) have been reportedin dogs, as has been delayed gastro-intestinal mo-tility in rats (23).

A sparing action of fat on vitamin B in ratshas been demonstrated by Evans and Lepkovsky(24). Conversely, exaggeration of the neuro-muscular manifestations of deficient dogs placedon a high carbohydrate diet was reported byFunk (25). In the light of these observationsit is interesting that in Case 1, while on a deficientdiet, a short period of high fat intake was accom-panied by some improvement in symptoms anddiminution in edema. When the carbohydratecontent of the diet was increased and the fat re-duced the improvement ceased.

SUMMARY

A patient, who received daily for 5 months aconstant quantity of an experimental diet ade-quate except for moderate limitation of vitamin B,developed signs of deficiency. Clinical signs andlaboratory evidence of altered function which de-veloped during deficiency disappeared followingaddition to the diet of especially prepared vitaminB fractions.

A second patient developed spontaneously simi-lar signs of deficiency which were relieved by sim-ilar vitamin B therapy.

The outstanding changes accompanying defi-ciency were: the appearance of definite symptoms,loss of weight, development of edema, fall inblood pressure, loss of gastro-intestinal tone andmotility, signs of neurological involvement and inone patient also an increase in pulse rate and amacrocytic type of anemia.

Vitamin fractions contained in yeast were nec-essary in addition to preparations of vitamin B,

so

CLINICAL VITAMIN B DEFICIENCY

and B2 for complete relief from the changeswhich accompanied deficiency.

The controlled observations made upon thesetwo individuals indicate that recognizable clinicalsigns may develop in otherwise normal personswhen the vitamin B content of the diet is onlymoderately limited. This clinical evidence of de-ficiency is accompanied by alterations in function,corresponding in many respects to changes de-scribed in vitamin B deficient animals.

I wish to acknowledge the kindness of Dr.George Cowgill in calculating the vitamin B1 con-tent of the experimental diet and in the advicegiven by him at the outset of this investigation.

I am indebted also to Dr. F. W. Sunderman forthe serum protein analyses, to Dr. L. Jonas forthe determinations of respiratory quotient, and toDr. P. H. Shiffer for his assistance in the fluoro-scopic examinations of the gastro-intestinal tract.

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3. Krogh, A., Turner, A. H., and Landis, E. M., A cel-luloid capsule for measuring venous pressures. J.Clin. Invest., 1932, 11, 357.

4. Landis, E. M., Jonas, L., Angevine, M., and Erb, W.,The passage of fluid and protein through the hu-man capillary wall during venous congestion. J.Clin. Invest., 1932, 11, 717.

5. Bourquin, A., and Sherman, H. C., Quantitative de-termination of vitamin G (B2). J. Am. Chem.Soc., 1931, 53, 3501.

6. Chase, E. F., and Sherman, H. C., A quantitativestudy of the determination of the antineuritic vita-min B. J. Am. Chem. Soc., 1931, 53, 3506.

7. Chick, H., Copping, A. M., and Roscoe, M. H., Eggwhite as a source of the antidermatitis vitamin B2.Biochem. J., 1930, 24, 1748.

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